Not Applicable.
Not Applicable.
This invention relates to a stereospecific synthesis of 24(S)-hydroxyvitamin D2 which is, in effect, a prodrug for 1xcex1,24(S)-dihydroxyvitamin D2, a natural metabolite of vitamin D2 that has been shown to have highly significant biologic effects, with a large therapeutic index when administered to a subject.
Vitamin D has long been established as having an important biological role in bone and mineral metabolism. For example, vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. More recently, other roles for vitamin D have come to light. Specific nuclear receptors for 1xcex1,25-dihydroxyvitamin D3, the natural hormone form of vitamin D3, have been found in cells of diverse organs not involved in calcium homeostasis. For example, Miller et al., 52 Cancer Res. (1992) 515-520, have demonstrated biologically active, specific receptors for 1xcex1,25-dihydroxyvitamin D3 in the human prostatic carcinoma cell line, LNCaP.
Still other metabolic conditions in which it has been suggested that vitamin D plays a role are immune response (see, e.g., U.S. Pat. No. 4,749,710 issued to Truitt et al.; U.S. Pat. No. 5,559,107 issued to Gates et al.; U.S. Pat. Nos. 5,540,919, 5,518,725 and 5,562,910 issued to Daynes et al.) and inflammatory response (see, e.g., U.S. Pat. No. 5,589,471 issued to Hansen et al.).
The discovery of active forms of vitamin D (M. F. Holick et al., 68 Proc. Natl. Acad. Sci. USA, 803-804 (1971); G. Jones et al., 14 Biochemistry, 1250-1256 (1975)), and active vitamin D analogs (M. F. Holick et al., 180 Science 190-191 (1973); H. Y. Lam et al., 186 Science 1038-1040 (1974)) in the 1970""s caused much excitement and speculation about the usefulness of these vitamin D compounds in the treatment of bone depletive disorders, and later in treatment of other disease states such as inhibition of malignant cell proliferation (see, e.g., U.S. Pat. No. 4,391,802 issued to Suda et al.; Skowronski et al., 136 Endocrinology (1995) 20-26).
However, it has been found that active vitamin D compounds, particularly 1xcex1-hydroxylated vitamin D3 compounds, can produce dangerously elevated blood calcium levels due to their inherent calcemic activity. Because of this toxicity, 1-hydroxylated vitamin D3 compounds can only be administered at dosages that are, at best, modestly beneficial, for example, in preventing or treating loss of bone or bone mineral content.
Considering the diverse biological actions of vitamin D and its potential as a therapeutic agent, a need exists for vitamin D compounds with greater specificity of activity and selectivity of action, e.g., vitamin D compounds with antiproliferative and differentiating effects but which have less calcemic activity than therapeutic amounts of the known compounds or analogs of vitamin D3.
Interest has grown in the use of so-called prodrugs or compounds which when administered are metabolized to known active vitamin D compounds. With this interest, the need for straightforward, efficient syntheses of vitamin D prodrugs, especially 24-hydroxylated vitamin D compounds, has intensified. Very few methods for 24-hydroxylation of vitamin D compounds have been reported. See, e.g., Jones et al., 202 Arch. Biochem. Biophys. (1980) 450-457 and Mawer et al., 83 J. Clin. Endo. Metab. (1998) 2156-2166 which disclose a biologically generated 24-hydroxyvitamin D2. Such biological syntheses compared to chemical syntheses are inefficient and require extremely large numbers of animal hosts to produce small amounts of desired compound. The art thus has yet to respond with a straightforward method for the synthesis of 24-hydroxyvitamin D compounds, particularly, 24-hydroxyvitamin D2.
The present invention provides a heretofore unmet need by the prior art, and specifically to the inherent inadequacies of prior synthetic processes for preparing 24-hydroxylated vitamin D compounds, specifically 24-hydroxyvitamin D2 wherein the hydroxyl group at the carbon-24 position is in the (S) configuration. The method of the present invention is distinguished by its simplicity in that it eliminates certain separatory steps of diastereomers characteristic of prior art processes.
The product compound of the method of the present invention is represented by formula (1), shown hereinafter, and is 24(S)-hydroxyvitamin D2 which has potent biological activity but low calcemic activity relative to the active forms of vitamin D3. Preferably, such compound is a 24-hydroxylated prodrug which is hydroxylated in vivo at the C-1 position to form 1,24(S)-dihydroxylated active vitamin D2.
The method of the present invention includes coupling of (S)-(+)-2,3-dimethyl-2-triethylsilyloxybutyraldehyde and a vitamin D phosphine oxide derivative to form a C-3 and C-24 diprotected trans-vitamin D2 which is then deprotected and irradiated to yield the 24(S)-hydroxyvitamin D2.
Other advantages and a fuller appreciation of the specific attributes of this invention will be gained upon an examination of the following drawings, detailed description of preferred embodiments, and appended claims. It is expressly understood that the drawings are for the purpose of illustration and description only, and are not intended as a definition of the limits of the invention.